We propose to establish a Center for Children's Environmental Health and Disease Prevention Research that addresses the concerns of a community living in the Tar Creek Superfund site of Oklahoma - an area highly contaminated by metals (lead, cadmium, iron, manganese, and others) in mining waste and populated by many residents of Native American descent. Our overall goal is to take a highly innovative and integrated approach to addressing a "real world" problem, i.e., the potential of the mixtures of metals that are present in "chat" (mining waste) to interact with each other in terms of exposure, absorption, dose, and adverse effects on the development of children. Our Center will pursue four Research Projects with the support of four Cores. Project 1 will be a community-based participatory epidemiologic study that examines biological markers of fetal and early childhood exposure to metals (lead, manganese, cadmium, and iron), their impact on measures of mental development, and their response to a quasi-experimental randomized trial of nutritional and behavioral interventions. Project 2 will assess the utility of size fractionation and sequential extraction studies for characterizing chat, conduct a nested case-control study of the determinants of high versus low burdens of metals amongst children participating in Project 1, and produce standardized "homogenized chat" for Projects 3 and 4. Project 3 will investigate the expression of binding and transporter molecules for metal transport and the corresponding pharmacokinetics of metals from the lung and gut to the blood, CNS and other organs as they relate to pregnant rats and their weanlings. Project 4 will examine the effect of pre- and neo-natal exposure to metals on neurochemical changes and neurobehavioral outcomes in rats. The effect of simple mixtures of metals will be compared with the effect of "homogenized chat" in both Projects 3 and 4. The potential effect of stress from living near toxic waste will be explored in Project 1 and the potential modifying effect of stress on metals neurotoxicity will also be explored in Project 4. Our Administrative, Analytical Chemistry, and Biostatistics Cores will enable us to fully integrate and support our research, and our Community Outreach and Translation Core will utilize an innovative portfolio of outreach activities developed in conjunction with a broadly-based Community Advisory Board to develop awareness and influence behaviors and health practices in order to prevent adverse health effects in children from exposure to metals in mining waste.